Aging and Disease最新文献

Ischemic stroke is a global health crisis associated with high mortality, long-term disability, and high healthcare costs. Microvascular dysfunction is pivotal in its pathophysiology. The brain microvasculature, far from a passive set of structures, is a complex system participating in multiple biological processes, including controlling angiogenesis, maintaining blood‒brain barrier (BBB) integrity, regulating cerebral blood flow (CBF) via neurovascular coupling, managing substance transport, and modulating central nervous system immune responses. Brain microvascular endothelial cells (BMECs) are central to the pleiotropic functions of the brain microvasculature; however, ischemia and hypoxia severely affect BMECs and disrupt microvascular functions. Angiogenesis is dysregulated, the BBB becomes permeable, the regulation of CBF becomes unbalanced, nutrient transport is disrupted, and immune modulation is disrupted. Targeted strategies to safeguard BMECs against ischemic-hypoxic injury have great potential for the treatment of ischemic stroke patients. This review comprehensively outlines the diversity of BMECs under normal conditions, delves into the effects of ischemia and hypoxia on these cells, and explores emerging protective strategies. By integrating these elements, this study offers a holistic perspective on the role of BMECs in ischemic stroke pathophysiology and aims to inspire future research in this crucial field.

Markers of necroptosis increase in neurons with neurodegenerative diseases and aging. Using a novel knockin mouse model that overexpresses the terminal necroptosis effector gene MLKL specifically in neurons (nMlkl-KI), we studied the impact of inducing necroptosis in neurons of young/adult mice on cognition. At 6-months of age, nMlkl-KI mice exhibited a 7-fold and 3-fold increase in MLKL monomer expression in the cortex and hippocampus, respectively. Correspondingly, MLKL-oligomer levels increased 3- to 4-fold in these brain regions, indicating necroptosis activation. The increased necroptosis was associated with an induction of neuroinflammation as shown by an increase in transcript levels of inflammatory markers and increased Iba-1 expression in the cortex and hippocampus. At 12-months of age, nMlkl-KI mice exhibited significant cognitive impairment compared to control mice as measured by a continuous home-cage discrimination learning with the Noldus PhenoTyper. For example, cumulative learning index during the reversal phase and cognitive flexibility were dramatically reduced in nMlkl-KI mice as compared to the control mice. Unbiased stereological analysis revealed no loss in neuronal number in the cortex and hippocampus, suggesting neuronal dysfunction rather than neuronal death was responsible for the reduced cognition observed in the nMlkl-KI mice. Transcriptomic analysis of the cortex revealed an upregulation of pathways associated with age-related neurodegenerative diseases (e.g., Parkinson's, Alzheimer's, Huntington's) as well as chemokine and TNF signaling in the nMlkl-KI mice. In contrast, the neuroactive ligand-receptor interaction pathway was downregulated. Collectively, these data show for the first time that the overexpression of MLKL in neurons leads to a loss in cognition in the absence of neuronal cell death, demonstrating that increased MLKL can interfere with neuronal functions involved in cognition.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely related inflammatory diseases that predominantly affect individuals over 50 years of age. The pathogenesis of two diseases is unclear. Accumulating evidence indicates that aberrant innate and adaptive immune responses underlie the pathogenesis of GCA and PMR. Monocytes/macrophages play an important role in the inflammatory processes through producing proinflammatory cytokines and chemokines, modulating molecular expression, colony-stimulating factors, proteolytic enzymes, and growth factors, and activating the JAK/STAT pathway. Clarifying the functions of monocytes/macrophages may help find targets for these diseases. Current research is investigating potential treatments such as proinflammatory cytokine blockers, anti-CXCR3 agents, competitive antagonists of GM-CSF activity, and JAK inhibitors in patients with GCA or PMR. In this study, we examine the role of monocytes and macrophages in the pathogenesis of GCA and PMR, identify potential drug targets, novel therapeutic strategies and future research directions.

Parkinson's disease (PD) is a highly prevalent neurodegenerative disorder, and current therapeutic approaches fail to prevent the progressive loss of dopaminergic neurons. To date, no disease-modifying therapies (DMTs) have been approved for PD. Developing effective DMTs remains the foremost objective in PD research. Here, we review the rationale for α-synuclein, LRRK2, GBA1, the PINK1-Parkin axis, and GLP-1R as potential therapeutic targets for PD. Additionally, we summarize the functional alterations observed in cellular organelles, including mitochondria, lysosomes, and the endoplasmic reticulum, in the context of PD. We also highlight the progress in drug development targeting these therapeutic candidates and the associated organelles. Furthermore, we discuss the advancements in stem cell-based therapeutic strategies in the field of PD research. It is believed that deepening understanding of disease mechanisms, combined with the development of novel technologies, offers promising potential for more effective solutions to this debilitating condition.

The gut harbors trillions of microbes that play essential roles in metabolism and immunological functions. The virome, an important but understudied component of the gut microbiota, comprises bacteriophages commonly referred to as bacterial viruses, among other inhabitants. Understanding the interplay between the gut virome and bacteria can illuminate the dynamics of microorganisms in both healthy and diseased states. This knowledge can open new avenues for treatment, such as phage therapy and microbiota modulation, which aim to restore balance in the gut and improve overall health. The composition and diversity of the gut microbiome and virome undergo significant changes, which have been linked to increased susceptibility to infections, chronic inflammation, and age-related disease. Exploring the gut virome's role in aging may provide insights into how viral and bacterial interactions influence immune senescence and gut resilience in the elderly population. This review provides an overview of the current understanding of the relationship between the gut virome, specifically phages associated with gut bacteria, and mechanisms of phage-host interactions, shedding light on how these factors affect and influence communities. Additionally, this review also explores the impact of the gut virome on gut resilience and its role in shaping and influencing the host's immune response. Maintaining a healthy gut requires a stable and robust virome. Therefore, future research on the virome is crucial for the development of microbe-based products that enhance human and animal health and aid in addressing specific diseases.

The fat mass and obesity-associated (FTO) gene is a key gene that has been linked to obesity and metabolic regulation. FTO single nucleotide polymorphisms (SNPs) significantly contribute to the pathophysiology of various multisystem diseases via epigenetic mechanisms. Although FTO has been extensively reviewed in the context of cancer, a comprehensive evaluation of its role in non-malignant diseases is currently lacking. This review aimed to systematically assess the molecular functions of FTO in the context of diseases other than cancer based on recent insights from the literature. Relevant studies were retrieved by systematically searching the PubMed database to explore the mechanisms through which FTO acts as a mediator of demethylation, its biological activities, and its functional roles in a spectrum of non-oncologic diseases. To explore pharmacological interactions, AutoDockTools 1.5.7 was used to simulate binding interactions between FTO and conventional therapeutic agents. Additionally, we conducted a bibliometric analysis using VOSviewer to visualize the frequency and co-occurrence of FTO-related terms, thereby helping to map research trends and knowledge gaps in the field. FTO regulates gene expression by modulating RNA methylation, particularly through the demethylation of N6-methyladenosine (m⁶A), thereby influencing RNA splicing, stability, and translation. This regulatory activity plays a major role in processes such as inflammation and fibrosis. Dysregulation of FTO has been implicated in several non-malignant diseases, including metabolic disorders, neurological diseases, and cardiovascular conditions. Computational docking studies showed that FTO exhibited strong binding affinity with two drugs and moderate affinity with eight others. Bibliometric analysis revealed high-frequency keywords and visualized research hotspots pertaining to FTO, providing valuable insight into current areas of scientific interest and potential future directions of study. FTO functions as a key epigenetic regulator in non-cancerous diseases and represents a promising biomarker and therapeutic target. Our findings underscore the importance of FTO-drug interactions and suggest that small-molecule FTO modulators may hold therapeutic value for managing a variety of non-oncologic conditions.

The possibility of developing precision therapies for neurodegenerative disease is tantalizing, and efforts are under way with several diseases, including Alzheimer's, Parkinson's and Huntington's disease. Despite strong basic neuroscience foundations and excellent clinical trial design, however, these efforts have been disappointing. We present an argument for a complementary approach of targeting the brain milieu in order to achieve disease-modifying effects in patients with or at risk of neurodegenerative disease. We suggest that a milieu-directed "brain health" approach can be applied across a range of at-risk individuals in a specific, quantitative, evidence-based manner. In support of this position, we present data from epidemiologic studies and clinical trials. We propose a program of rigorous research to validate and implement this complement to precision medicine which skeptics might call "imprecision medicine."

Older adults exhibit greater heterogeneity than younger adults in behavior, cognition, and brain, which may be influenced by a range of factors, including lifestyle. While previous studies have assessed brain heterogeneity by evaluating the dissimilarity of individual brain connectivity, further empirical evidence is needed to understand the factors behind brain heterogeneity in older adults. Using data from the 1000BRAINS study (N = 461, aged 55-85 years), we analyzed the individual variability (IV) of the functional (IVFC) and structural (IVSC) connectivity across 421 brain regions. We aimed to explore the relationship between network-wise and region-wise brain connectivity IV (i.e., both IVFC and IVSC), lifestyle, including psycho-social factors (e.g., self-reported smoking, physical activity, alcohol consumption, and social integration), and cognitive function via partial least squares correlation, stratifying analyses by age subgroups (55-64, 65-74, and ≥ 75 years), separately. Our results showed that higher connectivity IV was linked to lower social integration and/or higher smoking, and lower cognitive performance (e.g., episodic memory and executive control). For the network-wise analysis, we observed contributions from both IVFC and IVSC across eight networks, especially IVSC in the salience and ventral attention networks. Region-wise, significant contributions came primarily from the connectivity IV of specific brain regions (e.g., inferior frontal gyrus, right anterior cingulate cortex). This result pattern varied by age group. Connectivity IV was positively correlated with smoking in the age 65-74 group and negatively correlated with alcohol consumption in the age ≥ 75 years group. Overall, IVSC contributed more than IVFC with age. These findings suggest that unhealthy lifestyle and social isolation might be associated with differences in neural resources, which may be linked to increased individual brain heterogeneity and, in turn, to lower cognitive performance in older adults, supporting the revised Scaffolding Theory of Aging and Cognition (STAC-r).

Sensory loss has been associated with multiple adverse health conditions. However, the combined effect of visual and hearing impairment on frailty is unknown. The aim of this study was to examine the association between visual, hearing, and dual-sensory impairment and frailty prevalence. This cross-sectional study investigated 105,406 participants aged ≥39 years from the UK Biobank study. Visual acuity was measured with a chart, as the logarithm of the minimum angle of resolution (LogMAR); functional auditory capacity was measured with a digit triplet test, as the speech reception threshold in noise (SRTn). Dual sensory impairment was defined as the presence of both visual impairment (LogMAR &;gt 0.3 units) and hearing impairment (SRTn ≥ -5.5 dB SNR). To define the frailty syndrome, two methods were used, the frailty phenotype and the FRAIL scale. Analyses were conducted using logistic models adjusted for relevant confounders. Among the participants, 54.3% were women, with a mean age of 56.8 years (SD: 8.1, range 39 to 72). The prevalence of frailty was 3.5%, defined with the frailty phenotype, and 3.6%, using the FRAIL scale. For visual impairment, the OR (95% CI) of frailty was 1.51 (1.28-1.79) for the frailty phenotype, and 1.31 (1.10-1.57), for the FRAIL scale. For hearing impairment, in comparison with having normal hearing, the OR (95% CI) associated with insufficient and poor hearing were 1.32 (1.20-1.45) and 1.83 (1.53-2.19), respectively for the frailty phenotype, and 1.32 (1.19-1.46) and 1.93 (1.60-2.33) for the FRAIL scale. Estimates for the association between dual-sensory impairment and frailty were 2.22 (1.65-2.99) for the frailty phenotype, and 1.73 (1.23-2.42) for the FRAIL scale. Visual and hearing impairments were related to frailty. Having dual-sensory impairment was associated with twice the likelihood of frailty syndrome in comparison with having none of them.